Combination Therapy
in Acute Coronary Disease
Elizabeth Gabrielle PA-S
Lock Haven University
February 2009
Cardiovascular Disease
Leading cause of mortality and morbidity
worldwide.
 Estimated that 17 million people die of
cardiovascular disease each year.
 Incidences of major cardiovascular events
increase with age.
 Includes:

– High Blood Pressure, Coronary Artery Disease,
Heart Failure, Congenital Cardiovascular Defects, and
Stroke.
Coronary Artery Disease
(CAD)

Principle type of heart
disease.

In 2005:
– 445,687 people
died from CAD
– 68.3% of all heart
disease deaths.
Aspirin
(acetyl salicylic acid)
Works on both
cyclooxygenase
pathways.
 Permanently
deactivates
cyclooxygenase-1
pathway resulting in
antiplatelet effects.
 Antiplatelet drug of
choice.

Clopidogrel
(also known as Plavix)

Thienopyridine derivative

Selectively and irreversibly
inhibits the binding of
adenosine diphosphate (ADP).

Deactivates glycoprotein
IIb/IIIa complex.

Glycoprotein IIb/IIIa complex
allows fibrinogen binding to
platelet.

Inhibits platelet aggregation.
Current Indications

Individually aspirin and clopidogrel are
used for secondary prevention of
cardiovascular events.

Only indication of combination therapy is
for the treatment of patients with ACS
undergoing percutaneous coronary
intervention (PCI) with or without stent
placement.
Problem

With aspirin alone the relative risk reduction of death,
MI, and stroke is only approximately 20%.

How can we improve this?
Question

In adult patients 65 years old and older
with documented coronary artery disease,
without PCI, is daily aspirin therapy
alone compared to daily aspirin therapy
combined with clopidogrel more effective
at decreasing incidences of cardiac events?
Clinical Trials:
Combination Therapy
Three double blinded randomized controlled
trials.
 Trial 1: Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE)
 Trial 2: Clopidogrel for High Arthrothrombotic
Risk and Ischemic Stabilization, Management,
and Avoidance (CHARISMA)
 Trial 3: Clopidogrel and Metoprolol in Myocardial
Infaction (COMMIT)

CURE
Patients: 12,562 with non-ST elevation
acute coronary syndrome.
 Therapy: Clopidogrel 300 mg followed by
75 mg daily and aspirin 75-325 mg daily
vs. aspirin alone
 Outcome: Cardiovascular death, nonfatal MI, stroke at 9 months after onset of
treatment.

Conclusion:
CURE

Results:
– Cardiovascular Death, Non-fatal MI, Stroke
Combined Therapy 9.3%
Aspirin Alone Therapy 11.4%
Odds Ration 0.80 CI (0.72-0.90)
Evidence of benefit from combined
treatment.
 Mainly due to a decrease risk of non-fatal
MI and cardiovascular death.

Results:
CURE
CHARISMA
Patients: 15,200 patients with coronary
artery disease.
 Therapy: Clopidogrel 75 mg and aspirin
75-162 mg daily vs. aspirin alone for 28
months
 Outcome: Cardiovascular death, MI,
Stroke.

Conclusion:
CHARISMA

Results:
– Cardiovascular death, MI, Stroke
 Combined Therapy: 6.8%
 Aspirin Alone Therapy: 7.3%
 Odds ratio 0.93 (0.83-1.05)

Only a small reduction in the risk of
having a cardiovascular event during long
term follow up.
Results:
CHARISMA
COMMIT
Patients: 45,852 patients admitted to the
hospital within 24 hours of a suspected MI
without undergoing PCI.
 Therapy: Clopidogel 75 mg and aspirin
162 mg vs. aspirin alone for up to four
weeks.
 Outcome: Cardiovascular death,
reinfarction, Stroke.

Conclusion:
COMMIT

Results:
-Cardiovascular events, reinfarction, stroke
 Combined Therapy 9.2%
 Aspirin Alone Therapy 10.1 %
 Odds Ratio 0.91 (0.86-0.97)

There was a significant reduction in
death, reinfarction, and stroke.
What are the Risks?
Bleeding Risk

Clopidogrel
– Neutropenia
– Thrombocytopenic Purpura (TTP)
 Usually occurs within two weeks of drug initiation.
 High mortality if not treated promptly.
Bleeding Risk

Aspirin
– Twofold increase in the risk of upper-gastrointestinaltract bleeding with a dose of 75mg-100mg.
– Higher doses increase the risk of bleeding by a factor
of 4-10 because it causes more gastric lesions.
Combined Bleeding Risk

All studies concluded that there was an
increased risk of bleeding in the
populations receiving combined therapy
compared to those receiving only aspirin.

However, in patients who specifically had
ACS the benefits outweighed major
bleeding risks.
Application into Practice

Combination therapy of aspirin and
clopidogrel in standard long-term therapy
of patients with cardiovascular disease
should be considered. However it should
not be implicated until new data is
published.
Further Studies
1. Does the risk of bleeding increase with
long term therapy?
2. What is the optimal duration of
combination therapy?
Resources



1. Keller, TT, & Middeldorp, S (2008). Clopidogrel plus aspirin versus aspirin alone for
preventing cardiovascular diseaes (Review). Cochrane Database of Systematic Review,
3, Retrieved January 23, 2009,
http://www.mrw.interscience.wiley.com.navigatorlhup.passhe.edu/cochrane/clsys
rev/articles/CD005158/frame.html.
2. Bhatt, D., Fox, K., Hacke, W., Berger, P., Black, H., Boden, W., Cacoub, P., Cohen, E.,
Creager, M., Easton, D.,
Flather, M., Haffner, S., Hamm, C., Hankey, G.,
Johnston,C., Koon-Hou, M., Mas, J., Montalescot,
g., Pearson, T., Steg, G.,
Steinhubl, S., Weber, M., Brennan, D., Fabry-Ribaudo, L., Booth, J., Topal,
E.,(2006). Clopidogrel and Aspirin verus Aspirin Alone for the Prevention of
Atherothrombotic
Events. The New England Journal of Medicine, 354, Retrieved
January 23, 2009,
http://web.ebscohost.com/ehost/detail?vid=13&hid=9&sid=8f1b1dca-575f-4019-94e74819cd642a2a%40sessionmgr3&bdata=JmxvZ2lucGFnZT1sb2dpbi5hc3Amc2l0
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3. Lyseng-Williamson, Katherine, & Plosker, Greg (2006). Clopidogrel A Pharmacoeconomic
Review of its Use in
Patients with Non-ST Elevation Acute Coronary Syndromes. ADIS
International Limited , 24, Retrieved
January 23,
2009,
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Resources


4. Lutsep, Helmi (2006, June, 6). MATCH Results: Implications for
the Internist. The American Journal of Medicine, 119,
Retrieved January 23, 2009
http://www.mdconsult.com/das/article/body/1177220572/jorg=journal&source=MI&sp=16244386&sid=795343857/N/
536181/1.html?iss
n=0002-9343.
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Therapy with clopidogrel and aspirin. American Journal of
Health System Pharmacy , 65, Retrieved
January 23,
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